Effects of breast cancer resistance protein inhibitors and pharmaceutical excipients on decreasing gastrointestinal toxicity of camptothecin analogs.
OBJECTIVE
To investigate the effect of breast cancer resistance protein (BCRP) inhibitors and pharmaceutical excipients on reducing the biliary excretion of camptothecins (CPT), ameliorating delayed-type diarrhea and intestinal mucosa damage induced by CPT.


METHODS
The cumulative biliary excretion of irinotecan (CPT-11) and hydroxycamptothecin (HCPT) with or without BCRP inhibitors and excipients was investigated in rats. The gastrointestinal toxicity, assessed as the diarrheal score, body weight change and microscopic pathological damage was also determined in rats.


RESULTS
Breast cancer resistance protein (BCRP) exhibited important effects on the biliary excretion of CPT. Coadministration of BCRP inhibitors such as GF120918 and cyclosporin A reduced the biliary excretion of CPT-11 and HCPT. Pharmaceutical excipients such as Pluronic F68 and PEG 2000 stearate also showed inhibitory effects on BCRP and similarly reduced CPT biliary excretion. The observed gastrointestinal toxicity was ameliorated by coadministration of BCRP inhibitors and excipients compared with injection of CPT-11 and HCPT alone.


CONCLUSIONS
The use of excipients as inhibitors of BCRP is safe and relatively non-toxic, and may lead to important pharmacotherapeutic benefits by decreasing the gastrointestinal toxicity of CPT.
Zhang
Xin-xin
XX
Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
Pan
Wei-san
WS
Gan
Li
L
Zhu
Chun-liu
CL
Gan
Yong
Y
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000037:antagonists & inhibitors / Q000633:toxicity*; D001711:Biotransformation; D001943:Breast Neoplasms / Q000378:metabolism*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity*; D003967:Diarrhea / Q000139:chemically induced / Q000517:prevention & control; D005079:Excipients; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000972:Antineoplastic Agents, Phytogenic; D005079:Excipients; D009363:Neoplasm Proteins; D002166:Camptothecin